Pancreatic cancer represents the fourth most common cause of cancer-related mortality. Nonetheless, relatively little is known about the pathogenesis and epidemiology of this malignancy. In a previous R01 grant (R01CA86102), we pooled the resources of three large prospective cohort studies, the Nurses'Health Study, the Health Professionals Follow-up Study, and the Physician's Health Study to examine the epidemiology and pathogenesis of pancreatic cancer. In response to a NIH Program Announcement, PA-05- 040, "Molecular Approaches to Diet and Pancreatic Cancer Prevention," we now propose to extend our findings and our collaborations by including the resources of two additional large prospective cohort studies with extensive banked dietary data and biospecimens, the Women's Health Study and the Women's Health Initiative. Pooling of cases from these five large ongoing prospective cohort studies with long-term follow-up will allow a rigorous examination of hypotheses focusing on mechanisms of pancreatic cancer pathogenesis. We propose to examine 3 inter-related pathogenic pathways for pancreatic carcinogenesis: 1) energy balance, insulin and insulin-like growth factor signaling, 2) inflammation, and 3) vitamin D-related pathways. With the combined resources of these five cohort studies, we will study relevant exposures utilizing (1) prospectively collected data on diet, body habitus, physical activity, analgesic use, and other exposures (2) nutrient and hormonal biomarkers, and (3) genetic factors relevant to the pathways of interest. These exposures, plasma biomarkers, and genetic factors will be examined in relation to pancreatic cancer incidence as well as specific molecular alterations in pancreatic cancer specimens. The prospective design of these analyses will allow a rigorous examination of these risk factors while minimizing the potential biases that are inherent in retrospective studies of pancreatic cancer. By better understanding underlying mechanisms, dose-response relations, inter-relations among factors acting in similar pathways, variation in response due to genetic susceptibility, and specificity in associations to specific tumor markers, we can identify recommendations aimed at reducing the incidence and mortality from this highly lethal malignancy.